MDR/XDR-TB management of patients and contacts: challenges facing the new decade. The 2020 clinical update by the Global Tuberculosis Network

MDR/XDR-TB

management

of

patients

and

contacts:

Challenges

facing

the

new

decade.

The

2020

clinical

update

by

the

Global

Tuberculosis

Network

Giovanni

Battista

Migliori

*

,

Simon

Tiberi

,

Alimuddin

Zumla

,

Eskild

Petersen

,

Jeremiah

Muhwa

Chakaya

,

Christian

Wejse

,

Marcela

Muñoz

Torrico

,

Raquel

Duarte

,

Jan

Willem

Alffenaar

,

H.

Simon

Schaaf

,

Ben

J.

Marais

,

Daniela

Maria

Cirillo

,

Riccardo

Alagna

,

Adrian

Rendon

,

Emanuele

Pontali

,

Alberto

Piubello

,

José

Figueroa

,

Gabriella

Ferlazzo

,

Alberto

García-Basteiro

,

Rosella

Centis

,

Dina

Visca

,

Lia

D

’

Ambrosio

,

Giovanni

Sotgiu

,

the

members

of

the

Global

Tuberculosis

Network

a

ServiziodiEpidemiologiaClinicadelleMalattieRespiratorie,IstitutiCliniciScientificiMaugeriIRCCS,ViaRoncaccio16,Tradate,Varese,21049,Italy b

BlizardInstitute,BartsandTheLondonSchoolofMedicineandDentistry,QueenMaryUniversityofLondon,London,UnitedKingdom c

DivisionofInfection,RoyalLondonHospital,BartsHealthNHSTrust,London,UnitedKingdom

d_{DivisionofInfectionandImmunity,UniversityCollegeLondonandNIHRBiomedicalResearchCentre,UCLHospitalsNHSFoundationTrust,London,United} Kingdom

e

DirectorateGeneralforDiseaseSurveillanceandControl,MinistryofHealth,Muscat,Oman f

InstituteforClinicalMedicine,FacultyofHealthScience,UniversityofAarhus,Denmark g

ESCMIDEmergingInfectionsTaskForce,Basel,Switzerland h

TheInternationalUnionAgainstTuberculosisandLungDisease,Paris,France i

DepartmentofMedicine,Therapeutics,DermatologyandPsychiatry,KenyattaUniversity,Nairobi,Kenya

j_{DepartmentofInfectiousDisease,AarhusUniversityHospitalandSchoolofPublicHealth,FacultyofHealthSciences,UniversityofAarhus,Denmark} k_{ClínicadeTuberculosis,InstitutoNacionaldeEnfermedadesRespiratorias,CiudaddeMéxico,Mexico}

l

NationalReferenceCentreforMDR-TB,HospitalCentreVilaNovadeGaia,DepartmentofPneumology,PublicHealthScienceandMedicalEducation Department,FacultyofMedicine,UniversityofPorto,Porto,Portugal

m

SydneyPharmacySchool,FacultyofMedicineandHealth,TheUniversityofSydney,Sydney,Australia n

WestmeadHospital,Sydney,Australia o

Dept.ClinicalPharmacyandPharmacology,UniversityMedicalCenterGroningen,Groningen,TheNetherlands

p_{DepartmentofPaediatricsandChildHealth,FacultyofMedicineandHealthSciences,StellenboschUniversity,Tygerberg,SouthAfrica} q

TheUniversityofSydneyFacultyofMedicineandHealth,Sydney,NewSouthWales,Australia r

TheUniversityofSydneyMarieBashirInstituteforInfectiousDiseasesandBiosecurity,Sydney,NewSouthWales,Australia s

EmergingPathogensUnit,TBSupranationalReferenceLaboratory,SanRaffaeleScientificInstitute,Milan,Italy t

CentrodeInvestigación,PrevenciónyTratamientodeInfeccionesRespiratoriasCIPTIR,UniversityHospitalofMonterreyUANL(UniversidadAutonomade NuevoLeon),Monterrey,Mexico

u

DepartmentofInfectiousDiseases,GallieraHospital,Genova,Italy v_{TuberculosisDivision,DamienFoundation,Niamey,Niger} w

NationalHealthService(NHS)England,London,UnitedKingdom x

SouthernAfricaMedicalUnit,MédecinsSansFrontières,CapeTown,SouthAfrica y

CentrodeInvestigaçãoemSaúdedeManhiça(CISM),Maputo,Mozambique z

ISGlobal,BarcelonaCentreforInternationalHealthResearch,HospitalClínic-UniversitatdeBarcelona,Barcelona,Spain A

DivisionofPulmonaryRehabilitation,IstitutiCliniciScientificiMaugeri,IRCCS,Tradate,Italy B_{DepartmentofMedicineandSurgery,RespiratoryDiseases,UniversityofInsubria,Varese,Italy} C_{PublicHealthConsultingGroup,Lugano,Switzerland}

D

ClinicalEpidemiologyandMedicalStatisticsUnit,DepartmentofMedical,SurgicalandExperimentalSciences,UniversityofSassari,Sassari,Italy

* Correspondingauthor.

E-mailaddresses:giovannibattista.migliori@icsmaugeri.it(G.B.Migliori),simon.tiberi@nhs.net(S.Tiberi),a.i.zumla@gmail.com(A.Zumla),eskild.petersen@gmail.com (E.Petersen),chakaya.jm@gmail.com(J.M.Chakaya),wejse@dadlnet.dk(C.Wejse),dra_munoz@hotmail.com(M.MuñozTorrico),raquelafduarte@gmail.com(R.Duarte), j.w.c.alffenaar@umcg.nl(J.W.Alffenaar),hss@sun.ac.za(H.S.Schaaf),ben.marais@health.nsw.gov.au(B.J. Marais),cirillo.daniela@hsr.it(D.M.Cirillo),alagna.riccardo@hsr.it (adrianrendon@hotmail.com(A.Rendon),pontals@yahoo.com(E.Pontali),albertopiubello@yahoo.it(A.Piubello),josefigueroa@doctors.org.uk(J.Figueroa),

Gabriella.FERLAZZO@joburg.msf.org(G.Ferlazzo),alberto.garcia-basteiro@manhica.net(A.García-Basteiro),rosella.centis@icsmaugeri.it(R.Centis), dina.visca@icsmaugeri.it(D.Visca),liadambrosio59@gmail.com(L.D’Ambrosio),gsotgiu@uniss.it(G.Sotgiu).

1

ThemembersoftheGlobalTuberculosisNetworkarelistedinAppendixA. https://doi.org/10.1016/j.ijid.2020.01.042

1201-9712/©2020TheAuthors.PublishedbyElsevierLtdonbehalfofInternationalSocietyforInfectiousDiseases.ThisisanopenaccessarticleundertheCCBY-NC-ND license(http://creativecommons.org/licenses/by-nc-nd/4.0/).

ContentslistsavailableatScienceDirect

International

Journal

of

Infectious

Diseases

ARTICLE INFO Articlehistory:

Received10January2020

Receivedinrevisedform21January2020 Accepted22January2020 Keywords: MDR-TB XDR-TB Diagnosis Treatment Prevention Rehabilitationofsequelae ABSTRACT

The continuous flow of new research articles on MDR-TB diagnosis, treatment, prevention and rehabilitationrequiresfrequentupdateofexistingguidelines.Thisreviewisaimedatprovidingclinicians andpublichealthstaffwithanupdatedandeasy-to-consultdocumentarisingfromconsensusofGlobal TuberculosisNetwork(GTN)experts.

Thecorepublisheddocumentsandguidelineshavebeenreviewed,includingtherecentlypublished MDR-TBWHOrapidadviceandATS/CDC/ERS/IDSAguidelines.

Afterarapidreviewofepidemiologyandriskfactors,theclinicalpriorities onMDR-TBdiagnosis (includingwholegenomesequencinganddrug-susceptibilitytestinginterpretations)andtreatment (treatment design and management, TB in children) are discussed. Furthermore, the review comprehensivelydescribesthelatestinformationoncontacttracingandLTBImanagementin MDR-TBcontacts,whileprovidingguidanceonpost-treatmentfunctionalevaluationandrehabilitationofTB sequelae,infectioncontrolandotherpublichealthpriorities.

©2020TheAuthors.PublishedbyElsevierLtdonbehalfofInternationalSocietyforInfectiousDiseases. ThisisanopenaccessarticleundertheCCBY-NC-NDlicense(

http://creativecommons.org/licenses/by-nc-nd/4.0/).

Introduction

Multidrug-resistant (MDR-) and extensively drug-resistant tuberculosis (XDR-TB) still represent a challenge for clinicians andstaffoperatinginnationalTBprogrammes(Akkermanetal., 2019;Borisovet al.,2017,2019;Lange etal.,2019,2014;Nahid etal.,2019;WorldHealthOrganization,2019a,2019b;Miglioriand GlobalTuberculosisNetwork(GTN),2019).

AlthoughreviewsonMDR-TBdiagnosis,treatment,prevention andrehabilitationhavebeenrecentlypublished(Langeetal.,2014; Langeetal.,2019),theyarewarranted bytherapidturnoverof recommendationsandguidelinesfromtheWorldHealth Organi-zation(WHO)(WorldHealthOrganization,2019b)andscientific societies(Nahidetal.,2019).

Theaimofthisreviewistoprovidecliniciansandpublichealth staff an updated and easy-to-consult document arising from consensusofGlobalTuberculosisNetwork(GTN)experts.

Methods

Anon-systematicsearchoftheliteraturewasperformedusing thekeywords‘MDR-TB’/’XDR-TB’toidentifyaminimumsetofcore referencesfromelectronicdatabases(MEDLINE,PUBMED),existing guidelinesandgreyliterature.Awritingcommitteecomposedof internationally known experts was created, complemented by expertsfromthemembersoftheGTN(TreatmentandConsilium committeesandotherCommittees’chairs,seeacknowledgements) andconsensusonthecontentwasreachedaftermultipleroundsof revision (Akkerman et al., 2019; Borisov et al., 2019). WHO de_finitions were used (e.g. MDR-/XDR-TB, treatment outcomes) (Migliori and Global Tuberculosis Network (GTN), 2019; World HealthOrganization,2019a,2019b).Asthisreviewisnotaimedat duplicating WHO and other existing guidelines, the GRADE methodology (Nahid et al., 2019; World Health Organization, 2019b)wasnotused,andnoformalrecommendationsareprovided.

Figure1.Howtodesigntheregimenformultidrug-resistanttuberculosis.

InthetextandfigurewefocusmainlyontheATS/CDC/ERS/IDSAguideline,as-althoughlargelyconsistentwiththe2019WHOones-theyprovideadditionalclinicalelements withmainfocusonlow-TBincidencecountries.AdditionalminordifferencesincludelessfocusoninjectablesandtheWHOshorterregimen,morefocusontailoringthe regimentodrug-resistancesidentified,alargernumberofdrugsandaslightlydifferentprioritizationofthedrugs.

The2019WHOMDR-TBguidelinesrecommendthatall3GroupAdrugs(bedaquiline,linezolid,levofloxacin/moxifloxacin)and1GroupBdrug(clofazimine,cycloserine/ terizidone)areprescribed(4versus5drugsrecommendedbyATS/CDC/ERS/IDSAguidelines).Ifonly1or2GroupAdrugsareprescribed,bothGroupBdrugsshouldbe prescribed.Ifneeded,GroupCdrugs(ethambutol,delamanid,pyrazinamide,imipenem,meropenem,amikacin/streptomycin,para-aminosalycilicacid,ethionamide/ prothionamide)shouldbeadministered.

Inthisdocumentwerevisedtheupdatedavailableinformation ondiagnosis,treatmentandpreventionofMDR-TB.Thetimingof publicationallowedtheauthorstocapturethecontentoftheWHO rapidadviceonMDR-TB(WorldHealthOrganization,2019e)but not of the new WHO MDR-TB guidelines (not yet released, publicationexpectedinearly2020).Therefore,themainfocuswas ontheATS/CDC/ERS/IDSAguidelines(Nahidetal.,2019).Themain differencesbetweentheexistingWHOguidelinesandthe above-mentionedonesaresummarizedinthelegendofFigure1. Epidemiologyandriskfactors

Eliminationof TBby 2035willonly bepossibleif countries addresstheemergenceofdrug-resistant(DR)strainsof Mycobac-teriumtuberculosiseffectively.AccordingtotheWHO2018report, not all DR-TB cases are diagnosed (only 51% of people with bacteriologicallyconfirmedTB weretestedfor rifampicin resis-tance(RR)in2018),andnotallDR-TBcasesweretreated(onlyone inthreeoftheapproximatelyhalfamillionpeoplewhodeveloped MDR/RR-TB in 2018 were treated). DR-TB continues to be an important public health priority (World Health Organization, 2019d),andanestimated19millionpeoplearelatentlyinfected withMDR-TB(Knightetal.,2019).

Prevention of DR-TB remains a key priority and cannot be achievedbyearlydiagnosisandappropriatetreatmentalonebut also requires preventive therapy and effective vaccination. Moreover,themainriskfactorsforTBshouldbeprogrammatically addressed:theseincludepoverty,overcrowding,HIVco-infection, diabetes, alcoholism, smoking, immunosuppressive and other drugs.

DiagnosisofMDR-TB

TheEndTBStrategy(WorldHealthOrganization,2019d)calls fortheearlydiagnosisandtreatmentofallpersonswithanyform ofdrug-susceptibleorDR-TB.

Successfuldiagnosisand treatmentof MDR-/XDR-TBrely on universaldrug-susceptibilitytesting(DST)(Cabibbeet al.,2017; Miottoetal.,2017;WorldHealthOrganization,2019d).Increasing accesstoearlyandaccuratediagnosisusingaWHO-recommended rapid diagnostic test (WRD) (Table 1) is one of the main components of the TB laboratory-strengthening efforts in the EndTBStrategy.Intherecentyears,theadventofrapidmolecular techniques, based on nucleic amplification tests (NAATs) and sequencinghave representedan important breakthrough in TB diagnostics.

WHOapprovedHigh-throughputcentralizedMDR-TBtests Four PCR-based platforms, suitable for high laboratory throughput, have been approved by a WHO technical group (WorldHealthOrganization,2019c):(a)theRealTimeMTB(Abbott, Chicago,IL,UnitedStatesofAmerica[USA]);(b)theRocheCobas MTBassay(Roche,Basel,Switzerland),(c)theFluoroTypeMTBDR assay(HainLifescience, Nehren,Germany) and(d)the BDMax MDR-TBassay(BectonDickinson,NewJersey,USA).Eachplatform underwent a comparative analytical evaluation using a well-defined M. tuberculosis strainpanel totest their sensitivity for detectingM.tuberculosiscomplexandtheirabilitytodetectkey mutationsconferringresistancetorifampicinandisoniazid.There areconcernsthatadditionalstudieswillbeneededtoverifythe specificityofthenewassays,sincetheyusemulticopyornovel DNAtargets (orboth)for thedetectionof TB. Therefore,a 2nd phase oftesting willevaluate theclinicalvalidityof theassays through testing of the platforms in up to3 national reference laboratories in high TB burden settings. The results will be

comparedwiththereferencestandardsofculture,phenotypicDST, XpertMTB/RIFUltraandmolecularsequencing.

Next-Generationsequencing(NGS):apromisingtool

NGS is rapidly gaining interest as an affordable all-in-one diagnosticsolutionthatallowsforindividualisedtreatment.Unlike other TB diagnostic technologies providing partial information on drug-susceptibility limitedby a setof resistancemutations, NGS givescomprehensive genetic informationwitha varietyof applications ranging from diagnosis to surveillance of DR-TB. CurrentgenerationsequencingtechnologyreliesonDNA extrac-tionfromclinicalsamplesorclinicalisolates,librarypreparation made by collection of fragmented DNA with oligonucleotide adaptors, sequencing and data analysis. Despite the invaluable applicationofNGS,implementationofthis technologyhasbeen hampered,amongothercauses,byhighcostsofequipment,need for technicaltrainingand guidanceforclinicalinterpretation of generateddata.TheWHOhasrecentlyreleasedaguideprovidinga comprehensiveoverviewofworkflowandequipment,principles to best interpret genetic data, experience in using NGS in population-basedstudiesand,lastly,requirementsfor implemen-tationinlow- andmiddle-incomecountries.However,although promising, NGS will still need to achieve stringent regulatory approval,suchasfromtheWHO,tofacilitateitsimplementation intoroutinediagnostics(WorldHealthOrganization,2018a). HowtointerpretDST

WHO (World Health Organization, 2018b) defines universal accesstoDSTasrapiddeterminationforatleastrifampicin,and furtherDSTforatleastfluoroquinolonesamongallRR-TBpatients. Culture-based phenotypic DST methods are currently the gold standard for DR-TB detection, but these methods are time-consuming, and require sophisticated and well established laboratory infrastructure, qualified staff and strict quality and infectioncontrol.In addition,forsomedrugs(fluoroquinolones, rifampicin) molecular tests could be more predictive than phenotypictests.Traditionally,DSTforM.tuberculosishasrelied onthetestingofasingle,criticalconcentration(CC),whichisused todifferentiateresistantfromsusceptibleisolatesofM.tuberculosis andisspecificforeachanti-TBagentandtestmethod.Laboratory DSTstoanti-TBagentsservefourmainpurposes:(1)toguidethe choiceofaneffectiveregimen;(2)toconfirmthatDRhasemerged when a patient has failed to show a satisfactory response to treatment; (3) can be used for surveillance of emerging DR; (4)mayguidemanagementofclosecontactsoftheDR-TBcases, includingchildren.

Use of microtitre plates to determine minimal inhibitory concentrations (MICs)tomultipledrugsat thesametimeis an appealingtechnology andcouldbeusefullyadoptedtomonitor increaseofMICinapopulationexposedtonewdrugs.WHOwill releaseCConmicrotitreplatesin2020.

To perform phenotypic DST, mycobacteriaare often initially growninavarietyofsolidorliquidculturemedia.Bacterialgrowth on solid medium can be identified visually (i.e. by identifying characteristicgrowth)orbyautomateddetectionoffluorescence inliquidmedium.TheMGIT(mycobacterialgrowthindicatortube) automated M. tuberculosis culture system (Becton Dickinson Diagnostic Systems, Sparks, MD, USA) indicatesa reduction in theoxygen tensiontoconfirmthedetection of “M.tuberculosis complex”(MTBC)andexcludesthepresenceofanynontuberculous mycobacteriaorotherbacteriapriortoperformingDST.

WHOrecommendstheuseofrapidmolecularDSTastheinitial testtodetectDRpriortotheinitiationofappropriatetherapyforall TBpatients,includingnewandpreviouslytreatedones.

If RR is detected, rapid molecular tests for resistance to isoniazid, fluoroquinolones and amikacin should be performed promptlytoinformwhichsecond-linedrugscanbeusedforthe treatmentofRR-TB,MDR-TBandXDR-TB.

GenotypicDSTmethodssuchasNGSareattractivealternatives toculture-basedDSTmethodsgiventherapidityandthedetailed sequence information that can be generated for multiple gene regions associated with DR. However, until our knowledge of

the molecular basis of resistance improves, culture-based DST for other important second-line drugs including bedaquiline, linezolid,andotheragentswillstill needtobeperformed.One should considerperforming culture-basedDST for fl uoroquino-lonesandamikacinonlywhenresistanceissuspecteddespitethe absenceofpreviouslyidentifiedgeneticmutationsassociatedwith DRtothese medicines, ascommerciallyavailable rapidgenetic methods such as the second-line line-probe assays detect

Table1

NewTBdiagnosticsdevelopmentpipeline(adaptedfromWorldHealthOrganization,2019d).

NEWTBDIAGNOSTICS

TECHNOLOGIESENDORSEDBYWHO

MoleculardetectionofTBanddrugresistance

–XpertMTB/RIFandXpertUltraastheinitialdiagnostictestforTBandrifampicinresistance,Cepheid,USA

–LineprobeassaysforthedetectionofM.tuberculosis(MTB),isoniazidandrifampicinresistanceinacid-fastbacillismearpositivesputumorMTBcultures(FL-LPA),Hain Lifescience,GermanyandNipro,Japan

–TBLAMPfordetectionofTB,Eiken,Japan Nonmoleculartechnologies

–Interferongammareleaseassay(IGRAs)forthediagnosisoflatentTBinfection(LTBI)OxfordImmunotec,UK;Qiagen,USA Culture-basedtechnologies

–Commercialliquidculturesystemsandrapidspeciation

–Culture-basedphenotypicDSTusing1%criticalproportioninLJ,7H10,7H11andMGITmedia. Microscopy

–Lightandlight-emittingdiodemicroscopy(diagnosisandtreatmentmonitoring) Biomarker(MTBantigen)basedassays

–AlereDetermineTB-LAM,Alere,USA(TBdetectioninpeopleseriouslyillwithHIV)

ONTHEMARKET(NOTSUBMITTEDTOWHOFOREVALUATION)

MoleculardetectionofTBanddrugresistance –iCubateSystem,iCubate,USA

–Genechip,TBdrugresistancearray,CapitalBio,China –EasyNATTBDiagnostickit,UstarBiotechnologies,China

TECHNOLOGIESUNDERDEVELOPMENT

MoleculardetectionofTBanddrugresistance –GendriveMTB/RIFID,Epistem,UK –XpertXDR-TBcartridge,Cepheid,USA –TruArrayMDR-TB,Akkoni,USA –INFINITIMTBAssay,AutoGenomics,USA

–FluoroTypeXDR-TBassay,HainLifescience,Germany –MeltProTBassay,ZeesanBiotech,China

–QuantuMDx,POC,UK TestsforlatentTBinfection

–Diaskintest,Generium,RussianFederation –C-Tbtest,SerumInstituteofIndia,India

SCHEDULEDFORWHOEVALUATIONIN2019/2020

MoleculardetectionofTBanddrugresistance

–Moleculartechnologiesforgenotypicdrugresistancetesting(includingsequencingtechnologies) –FluoroTypeMTBDR,HainLifescience,Germany

–m2000RealTimeMTBSystem,Abbott,USA –BDMaxMDR-TB,BectonDickinson,USA

–Rochecobas1MTBsystem,RocheDiagnostics,Basel,Switzerland Radiology

–Computeraideddetection(CAD)

WHOPOLICYUPDATESSCHEDULEDFOR2019/2020

MoleculardetectionofTBanddrugresistance

–XpertMTB/RIFUltrafordetectionofTBandrifampicinresistanceinpulmonary,extrapulmonaryandpaediatricsamples,Cepheid,USA –Truelab/TruenatMTB,Molbio/bigtecDiagnostics,India

Culture-baseddrugsusceptibilitytesting

–SensititreTMMYCOTBIplate;ThermoFisherScientificInc.,USA

MDR-TB:multidrug-resistanttuberculosis;XDR-TB:extensivelydrug-resistanttuberculosis;IGRAs:interferon-gammareleaseassays;LTBI:latenttuberculosisinfection; TB-LAM:tuberculosislipoarabinomannanassay.

approximately85%offluoroquinolones-ortwothirdsof amino-glycosideresistancemutations.

DeterminingcriticalconcentrationsforDST

DST results should be able to clearly differentiate between susceptible and resistant,and should help physiciansprescribe effective anti-TB therapy. DST for second-line anti-TB agents shouldbebuiltonthefoundationofreliable,quality-assuredfi rst-line DST. In 2018, critical concentrations were revised or establishedforperformingDSTfortheWHOGroupAdrugsthat are strongly recommended in the treatment of DR-TB. These include the later-generation fluoroquinolones (levofloxacin and moxifloxacin),bedaquiline,andlinezolid.Acriticalconcentration for the oral core agent clofazimine was established for MGIT medium only. Criticalconcentrations for the GroupC (addon) agentswereestablishedorvalidatedfordelamanid,amikacin,and pyrazinamide. Knowledge of pyrazinamide susceptibility can inform decisions on the choice and design of effective DR-TB regimens.Culture-basedpyrazinamidephenotypicDSTisdifficult toperformandcanproduceunreliableresults.Currently,BACTEC MGIT960liquidculturemethodistheonlyWHO-recommended methodforpyrazinamideDST, eventhoughahighrateof false-positiveresistanceresultshasbeenreportedinsomelaboratories. In a quality-assured laboratory,pyrazinamideDST in MGITcan be performed reliably and reproducibly. The lack of WHO-recommendedmoleculartesttodiagnosepyrazinamideresistance ahead of treatment start implies that even where pyrazina-mideDSTisavailable,theresultsusuallyonlybecomeaccessible aftertreatmenthas beeninitiated. Thedetection of resistance-conferringmutationsinthepncAgeneusingDNAsequencingis the most reliable method for rapid detection of pyrazinamide resistancealthoughthereisemergingevidenceofmutationsother thanpncAconferringpyrazinamide-resistance.

Treatment for MDR-TB is increasingly becoming more individualised as a result of innovations in diagnostics and growingscientificunderstandingofthe molecularbasisfor DR and the pharmacokinetics and pharmacodynamics of TB

medicines. Availability of new NGS-based tests able to detect mutationsassociatedtoDRonmultipletargetsmakesitpossible topredictresistancetofirst-andsecond-linedrugsfromsmear positiveclinicalsamples.Twosignalsareclearfromthecurrent scientificevidenceassessment:(a)thefeasibilityofeffectiveand full-oraltreatment regimensfor mostpatients;(b)theneedto ensure that pre-XDR and XDR are excluded (at least to the fluoroquinolones and amikacin) before starting patients on treatment, especially for the shorter MDR-TB regimen. When countries switch to all-oral regimens, the need to exclude resistancetoamikacinwillbelessuseful.

DSTshouldbeperformedatthetimeof treatmentinitiation (Figure 2) against the drugs for which a reliable method is available.IfbaselineDSTisnotpossible,DSTshouldbeperformed on the first positive culture isolated from the patient during treatment monitoring. Positive cultures isolated from patients duringtreatmentmonitoringshouldbestoredfrozeninglycerol.If DRortreatmentfailureissuspected,phenotypicDSTandNGS,if available,shouldbeperformedtocollectdataonmutationsthat maybeassociatedwithTBDR,especiallyforthenewerdrugs.

Inresponsetothischallenge,high-TBburdencountriesmust upgrade and streamline their laboratory networks. Molecular techniquesshouldreplacephenotypicmethodsforinitial diagno-sis and detectionof DR,while traditional cultures will still be neededduringfollow-uptodetectviablebacilli.Atleastatcentral levelcapacity toperformDSTfor bedaquiline,linezolid, clofazi-mine and delamanid should be established. The Xpert system shouldbeintroducedatpoint-of-carefacilitiesforrapiddetection of RR, and Line ProbeAssays (LPAs) candiagnose MDR-TB and XDR-TBinjustacoupleofdays,allowingfortheearlyinstitutionof effectivetreatment.

Howtodesigntheregimen

Apatient-tailoredclinicalstrategyfocusedongoodadherence isnecessarytoachievehightreatmentsuccessratesforMDR-TB patients (Figures 1 and 2,Table 1). In particular, the need to individualizetreatmentregimenshasbeenrecentlyemphasized,

Figure2.Clinicalmanagementofpatientswithmultidrug-resistanttuberculosis.

MDR-TB:multidrug-resistanttuberculosis;WGS:wholegenomesequencing;LPA:lineprobeassay;DST:drug-susceptibilitytesting;DOT:directlyobservedtherapy;ETH/ PTH:ethionamide/prothionamide;PAS:para-aminosalicylicacid;LZD:linezolid;QTcinterval:correctedmeasureofthetimebetweenthestartoftheQwaveandtheendof theTwaveintheheart’selectricalcycle;BDQbedaquiline;CFZ:clofazimine;DLM:delamanid.

takingintoaccounttheDRpatternoftheputativeM.tuberculosis strain.

Treatmentsuccessdependsontheabilityofthetreatingteamto monitorandmanageadverseeventsandconcomitant comorbid-ities (e.g., HIV-infection, diabetes mellitus, alcoholism, etc.), potentialdrug-druginteractions,patient’spreferencesand tolera-bility (e.g., administration of second-line injectable drugs) in additiontodesigninganeffectivetreatmentregimen(Akkerman etal.,2019;Borisovetal.,2019;Nahidetal.,2019;WorldHealth Organization,2019b).Inindividualswithpauci-bacillarydisease (e.g., children, HIV co-infected individuals) and without the con_firmation of a speci_fic DST pattern, the regimenshould be tailoredtotheDSTfindingsofthepotentialindexcaseorthe MDR-TB epidemiology of the geographical area where the patient resides(Nahidetal.,2019).

However,asdesigningtheregimenandmanagingtheMDR-TB patientisdifficult,amulti-disciplinaryapproachisrecommended, assisted bya MDR-TB Consilium,MDR-TB cohort or equivalent expertsupport.InadditiontoregionalandnationalTBConsilia,a supranational cost-free and multilingual platform is available offering validated and vetted advice in clinical management, within 48h (Global TB Consilium: http://www.waidid.org/site/ workinggroups). According totheATS/CDC/ERS/IDSA guidelines theregimenshouldincludefivedrugsduringtheintensivephase andfourdrugsduringthecontinuationphase(Nahidetal.,2019), withatreatmentdurationbetween15and21monthsafterculture conversionforMDR-TBandbetween14to24monthsforpre-XDR/ XDR-TBpatients(Nahidetal.,2019).Theintensivephase(aimedat significantlydecreasingthebacillaryburden)shouldrangefrom5 to7months(Nahidetal.,2019)aftercultureconversionaccording tothesamedocument.

AccordingtotheconsolidatedWHOMDR-TBguidelines(World HealthOrganization,2019b),4oraldrugsarerecommendedinthe intensivephaseandatleast3inthecontinuation phaseoftreatment, withatotaltreatmentdurationof18–20monthsformostpatients. InMDR/RR-TBpatientsonlongerregimens,atreatmentdurationof 15–17 months after culture conversion is suggested for most patients,withanintensivephaseof6–7monthswhenthelonger regimenincludesamikacinorstreptomycin:thetreatment dura-tionsmentionedabovemaybemodifiedaccordingtothepatient’s responsetotherapy(WorldHealthOrganization,2019b).

Six consecutive steps are recommended (Figure 1) by the recentATS/CDC/ERS/IDSAguidelines,publishedin2019.Stepone impliestheprescriptionofonelater-generationfluoroquinolone (i.e.,levofloxacin,moxifloxacin),followedby(Step2)two high-prioritydrugs(i.e., bedaquilineand linezolid).Step3 includes twootherhighlyeffectivedrugs(i.e., clofazimine,cycloserine). The need for Step 4 depends on the strain’s susceptibility pattern:in caseof DRtoone ormoreof theabove-mentioned drugsandtheimpossibility tohave 5active drugsweneedto chooseoneinjectabledrug(amikacinorstreptomycin).Ifneeded orafulloralregimenispreferred,injectablesshouldbereplaced bydelamanid,pyrazinamide,orethambutol(Step5:thelasttwo medicinesonly if con_firmed susceptibility to these agents). A complicatedDRpatternpreventingtheprescriptionofa5-drug regimenbasedontheabove-mentionedmedicinesimpliesthe need for different agents (Step 6). The ATS/CDC/ERS/IDSA guidelines assign lower priority to the administration of ethionamide/prothionamide, imipenem/meropenem plus clav-ulanate,para-aminosalycilicacid,high-doseisoniazid,basedon their poor effectiveness to decrease mortality or inability to increasethetreatmentsuccess rate,orrouteofadministration (Nahidet al., 2019).Capreomycin, kanamycin, macrolides,and amoxicillin/clavulanicacid(thelattershould only be adminis-tered with a carbapenem-containing regimen) are no longer recommended(strongrecommendation).

Withregardtoinjectables,theyrequiremoretimetoprepare, administer,andmonitor;consumepatientandstafftime;areless liked by patients; and invariably raise costs. Amikacin is an effectivedrugagainstDRtuberculosisasdemonstratedinprevious IPDmetanalyses.However,ithasbeenreplacedbymoreeffective, oralandlesstoxicmedications;thisdoesnotmeanthatitcannot beusefulinsettingswhereitcanbeadministeredandmonitored safely. Recentlypublishedand unpublishedexperiences suggest carbapenems are effective in patientswith complex resistance profiles(Arbexetal.,2016;TheCollaborativeGroupforthe Meta-Analysis of Individual Patient Data in MDR-TB treatment-2017 etal.,2018;Tiberietal.,2016a,2016b).

Clinicalmanagement

AstheclinicalmanagementofMDR-TBpatientsiscomplicated (Figure2),anadequatelyplannedmanagementmodelbalancing available specialized resources and prevalence of disease is required. Thus, in countries with low prevalence and high resources (e.g. Western European countries, North America) it shouldideallybecarriedoutinMDR-TBreferencecentres,where skilled clinicians can operate in the presence of adequate infrastructure and pathways (infection control, palliative care, quality-controlled laboratory, access to cohort and consilium advice)(Migliorietal.,2019).Conversely,insettingswithlimited resourcesandhighprevalenceofMDR-TBadecentralizedmodelof carehasproventobeeffective,andisadvisable(Lovedayetal., 2018).In thislattercase,onlycomplicatedcasesarereferredto specializedcentresorproposedtolocal/internationalTBconsilia. DetailsontheuseofmoleculartestingandDSTaswellasonthe principlestodesignaneffectiveregimentreatmentdurationare providedinFigures1and2andintheprevioussections(Nahid etal.,2019;WorldHealthOrganization,2019b).

Treatment design shouldbebased onlyonprovenor highly probable drug susceptibility, ‘in-vitro’ or based onclinical and epidemiological information (e.g., the DR pattern of the index patient,orthemostupdatedepidemiologicaldataontheprevalent drugresistancesinaspecificsetting).

Giventherelativedifficultyandcostofsamplingpatientsona weekly basis and thelack of approvedbiomarkers, durationof treatment continues to be an amalgamation of clinical and radiologicaldata,a lackof positivemicrobiology,and erringon thesideofcaution.

Moreresearchisnecessarytogiveafinalverdictontheefficacy/ effectivenessofstandardizedshorter-courseregimenslasting12 months in comparison with effective longer all-oral regimens (Nahid et al., 2019). It is possible that the use of new drugs, particularlyinsomeformsofpauci-bacillaryorextrapulmonaryTB mightrequire,inthefuture,shorterregimensthanmoresevere cavitaryforms;however,moredataisneededtodictateshorter durationsoftreatment.

WHOrecommendstheuseof shorter9–12month regimens (4–6 months with amikacin-moxifl oxacin-ethionamide[prothio-manide]-clofazimine-pyrazinamide-high dose isoniazid/etham-butol/5 months with moxifl oxacin-clofazimine-pyrazinamide-ethambutol) whenthe DRpatternis not complicatedbased on thefindingsoftheSTREAMtrial(Nunnetal.,2019).Thisshouldbe usedonlyfortheregimensincludinginjectables,butafterarecent literaturereview,WHOhasupdatedrecommendationsandisnow phasing out the shorter injectable-containing regimens and recommendingashorterall-oralbedaquiline-containingregimen foreligibleMDR/RR-TBpatientsunderspecificconditions(World HealthOrganization,2019e).However,duetothelonghalf-lifeof bedaquiline,patientsstartedonanall-oralregimenlostto follow-upmaybeexposedtopotentialbedaquilinemonotherapy,witha potential risk of developing DR. Recent evidence suggeststhat

adequate management of injectables in specific patients mini-mizesadverseevents(Borisovetal.,2017;Piubelloetal.,2020).

Following the results of the NIX TB trial (World Health Organization,2019e)andtheUSFDA(FoodandDrug Administra-tion)approvalinpatientswithXDR-TB, a shorterregimenwith bedaquiline,pretomanidandlinezolid(BPaLregimen)maybeused (underoperational researchconditions and noprevious useof bedaquilineandlinezolid)asanalternativetothelongerregimen. If pretomanid-containing regimens are used under operational conditions, capacity to test for the drug should be equally considered.

Inselectedpatientswithstrongriskofrelapseandtreatment failure(andlocalisedpulmonarysequelae), electivepartial lung resection(e.g.,lobectomy orwedgeresection)hasbeen recom-mendedinadditiontoanadequatelydesignedMDR-TBregimen (Nahidetal.,2019).

Duringfollow-upclosemonitoringofthetreatmentresponseis recommended:patientsshouldbeassessedclinically(symptoms andclinicalsignsrecovering,includingweightgainforchildren), radiologically,and bacteriologically(culture positivityevaluated monthly). In the case of culture remainingpositive after three monthsoftreatment,phenotypicDSTshouldberepeatedtodetect ifnewDRhasoccurred(Nahidetal.,2019).Whendrug-susceptible DSTdoesnotmatchwiththepatients’clinicalprogress,underlying DRormalabsorptioncanberesponsible,andfurtherinvestigations liketherapeuticdrugmonitoring(TDM)mightbenecessary.

Duringfollow-up visits,patientsshouldthoroughly be ques-tionedabouttheoccurrenceofdrug-relatedadverseevents:they coulddecreasepatient’sadherence,increasingtheprobabilityof new DR. Adverse events should be notified to the national programme,ideallywithinacomprehensiveaDSM(active drug-safety monitoring and management) system (Akkerman et al., 2019;Borisovetal.,2019).

TDMishelpfultodetectlowdrugexposureincaseoflackof responseordrug-relatedadverseevents(Nahidetal.,2019).Based onthemeasureddrugconcentration,drugdosagescanbeadapted to optimize the treatment. Proactive use of TDM can help to preventdrug-relatedcomplicationsinpatientswithriskfactorsfor eitherloworhighdrugexposure(Nahidetal.,2019;WorldHealth Organization,2019b).TDMhasbeenrecommendedfor patients withgastrointestinal problems(e.g. affecting absorptionof the drug),renalorhepaticproblems(e.g.lowclearanceofthedrug), comorbidities like diabetes type2 and HIV or drug-drug inter-actions(Nahidetal.,2019).Forthemaximumbenefit,samplesfor TDMneedtobecollectedattherighttimeandintherightmanner, analyzedinatimelyfashionandcorrectlyinterpreted,resultingin a doseadjustment recommendation to the clinician (Alffenaar et al., 2019). Clearly, a good understanding of bioanalytical proceduresandclinicalpharmacologicallyisrequiredtodevelop aTDMforaprogrammaticsetting(Alffenaaretal.,2019).Theuseof differentsamplingstrategies likesalivaand driedbloodspotin additiontoplasmaorserumwillallowasimplesemi-quantitative screeningtodetectlowdrugexposureaswellaspreciseTDMin thosewithdetectedlowexposure(Alffenaaretal.,2019b,2019a). A patient-centered approach is recommended after the diagnosisofMDR-TB,assuggestedbytheWHOEndTBStrategy initsfirstpillar(WorldHealthOrganization,2015a;WorldHealth Organization,2019d).Clinicians shouldclearlyexplaintherisks associatedwiththedisease(e.g.,transmissionofM.tuberculosis strainsincaseofinappropriatetherapy),andwiththetherapy(e.g., potentialoccurrenceofadverseevents,importanceofadherenceto treatment).Patientsshouldbeactivelyinvolvedinthechoiceofthe drug regimen (use of injectable-containing versus full-oral regimen),andinthemanagementofconcomitantcomorbidities and potential drug-druginteractions (Nahidet al.,2019; World HealthOrganization,2019b).

The time-span of isolation of MDR/XDR patientsis often a matterofdebateinTBconsilia,andunequivocalguidelinesfor de-isolationofpatientsingeneralaremissing(Petersenetal.,2017). WHOandCDCguidelinesmaybeinterpretedasrequiringMDR-TB patientstobeisolatedaslongastheyareculture-positive,butthe recentconsensusdocumentfromWHOEuropehasreviewedthe literatureextensivelyandhasshowntheimportanceofeffective treatmentfordurationofisolation(Migliorietal.,2019).Sputum maybeculture-positivefor1-2monthsaftertreatmentinitiation (Fitzwateretal.,2010)andafterwardsthereisa2-monthdelayfor thecultureresulttocomeoutasnegative,unlessliquidculturesare inuse,implying3-4monthsofisolation,perhapshospitalization. Yet, also someMDR-TB patientsare no longer infectious after 2 weeks of effective treatment (Dharmadhikari et al., 2014), althoughspecialcautionshouldbetakenincaseofhighly smear-positive cases – as in cavernous disease (Dharmadhikari et al., 2014;Imperialetal.,2018;Menzies,1997;Petersenetal.,2017; Migliorietal.,2019).Thesepatientsremaininginfectiousaslongas theyaresputumsmearorculturepositiveseemstobeunfounded, and although MDR-TB patients remain culture-positive longer (Telzaketal., 1997),thisisaresultofbeingonineffectivetreatment initially.Onceaneffectivetreatmenthasbeenestablished,MDR-TB patientsarealsolikelytoreduceinfectiousnessrapidly.Therefore, 3–4monthsofisolationis notwarranted(Petersenetal.,2017; Rouillonetal., 1976)whileisolationbeyond2weeksoftreatmentis warrantedbecauseoftheriskofnon-effectivetreatmentsincefull susceptibilityresultsmaynotbeavailableatthetimeoftreatment initiation.NewRNA-basedmoleculartestsmayinthefuturebe usedtomonitorinfectiousnessandresponsetotreatmentwithout thedelaylinkedtotheuseofculture.

ManagementofchildrenwithMDR-TB

Giventhedifficultyofmicrobiologicalconfirmationinchildren, MDR-TBisoftenapresumptivediagnosis,although microbiolog-icalconfirmationshouldalwaysbepursued.UseofthenewXpert Ultraisadvisedinchildrengivenincreasedsensitivityinpatients with pauci-bacillary disease. (Zar and Nicol, 2019). Children diagnosed onclinical grounds,following recent (inthepast 12 months) close contact with an infectious MDR-TB sourcecase, shouldbetreatedaccordingtotheDSTresultsofthelikelysource case.Theprinciplesoftreatmentaresimilartothosearticulatedfor adults,buttherationaleforusinginjectable-freeregimensiseven stronger given thedevastating consequences of hearingloss in early life (Seddon et al., 2018).Although the same drugs used inadultsareusedinolderchildren,bedaquilineiscurrentlynot advisedin childrenlessthan 6years ofage(<15kg) giventhe absenceofpharmacokineticandsafetydata(TheSentinelProject forPediatricDrug-ResistantTuberculosis,2018).Bedaquilinemay bereplacedbydelamanidinchildren3-6yearsofage,butcannot begiventochildren<3yearsofage(<10kg)forthesamereason (HuynhandMarais,2019;WorldHealthOrganization,2016).In youngchildren(<3yrsofage)alternativesecond-linedrugsshould beconsidered(Schaafetal.,2018).Childrenwithpauci-bacillary disease may sometimes be treated for a shorter duration (19–15months)ifanadequateregimenisgiven,andthetreatment response is good and is well tolerated. Child-friendly drug formulationsshouldbeusedwheneverpossible,andallrelevant co-morbidities, such as HIV co-infection and malnutrition, consideredand addressed.In childrenwithMDR-TBmeningitis, carefulconsiderationshouldbegiventocentralnervoussystem andcerebrospinalfluidpenetrationofthevariousdrugs(Huynh etal.,2019).Withoptimalmanagement,excellentoutcomeshave beenreportedinchildrenwithMDRand evenXDR-TB(Harausz etal.,2018).

Table2

Evidenceoftreatmentoflatenttuberculosisinfectionincontactsofmultidrug-resistanttuberculosis.

Study/trial Studypopulation/Aim Design/treatment Adverseeventsandoutcome Reference

TrialTB-CHAMP

HouseholdMDRTBcontacts;onlychildren

<5yearsold–SouthAfrica(enrolling) Aim:Toevaluatetheefficacyof levofloxacinvs.placeboforpreventionof MDR-TBinyoungchildrenfollowing householdexposure

Multi-centre,randomizeddoubleblind placebo-controlledtrial

6monthsofparent-administeredoral levofloxacinonceperday,vs6monthsof placebointhecontrolgroup;followedfor18 monthsaftertreatmentcompletion

Notreported WHOInternational

ClinicalTrialsRegistry Platform,identifier: ISRCTN92634082

TrialPHOENIx MDR-TB

HouseholdMDRTBcontacts;allages– multiplecountries(enrolling) Aim:Toevaluatetheprotectiveeffect delaminidvs.isoniazidforpreventionof M/XDR-TBfollowinghouseholdexposure

Unblinded,randomizedcomparativetrial Compareefficacyandsafetyof26weeksof delamanidversus26weeksofisoniazidfor preventingconfirmedorprobableactiveTB during96weeksoffollow-upamong high-riskhouseholdcontactsofM/XDR-TBadults

Notreported ClinicalTrials.gov

identifier: NCT03568383

V-QUINMDR TRIAL

HouseholdMDRTBcontacts;allages– Vietnam(completedenrolling) Aim:Toevaluatetheefficacyof levofloxacinvs.placeboforpreventionof MDR-TBfollowinghouseholdexposure

Double-blindparallelgroupRCT 6monthsofself-administeredoral levofloxacinonceperday,vs6monthsof placebointhecontrolgroup;followedforat least24monthsaftertreatmentcompletion

Notreported <**AustralianNew ZealandClinicalTrials Registry(ANZCTR), identifier:

ACTRN12616000215426 Meta-analysis Meta-analysisoftreatmentofLTBIusing

PICOquestionsfollowingCochrane procedures

ToassesswhethertreatmentofLTBIfrom MDR-TBcontactsissignificantlyassociated withlowertuberculosisincidence, comparedwithnomedicaltreatment

Themosteffectiveregimenincludeda fluoroquinolonecombinedwith ethionamide

Themostcost-effectiveregimenincluded fluoroquinolone/ethambutol,followedby fluoroquinolonealone,thenby pyrazinamide/ethambutol

Pyrazinamideregimensreported upto66%adverseevents Theregimenwasconsidered cost-effective.

Marksetal.(2017)

Caseseriesof close MDR-TBcontacts

PreventdevelopmentofclinicalMDR-TB FiftycontactsofHIV-andMDR-TBpatients treatedwithmoxifloxacin;30patients completedtheregimeninNewYorkCity

Threediscontinuedtreatment becauseofgastrointestinal symptoms. Trieuetal.(2015) Caseseriesof close MDR-TBcontacts

TwelveconsecutivecontactstoanMDRTB case

Theaimofthestudywastodescribethe adverseeventsrelatedtocombined pyrazinamideandethambutoltotreatLTBI

Observationalcaseseries,Theregimens consistedofpyrazinamide(234mgperKg BW)andethambutol(174mgperKgBW)

Treatmentwasdiscontinuedin sevencases(58%)afteramedianof 119days,duetohepatotoxicityin sixcases(ALTorASTelevationmore thanfourtimestheuppernormal limit),andgastrointestinal symptomsinonecase

Younossianetal. (2005)

Openlabel, comparative study

186childrenwereincludedascontactsof 164MDR-TBsourcepatients

Theyunderwent12monthsfollow-upin SouthAfrica

Ofloxacin(15–20mg/kgBWdailyplus ethambutol(20–25mg/kgBWdaily),or isoniazid(15–20mg/kgBWdaily)for 6months

7(3.7%)childrendevelopedgrade3 adverseevents

Onechilddiedand6developed activeTB(ofwhom5hadpoor adherence)

Seddonetal.(2013)

Caseseriesof close MDR-TBcontacts

119contactsofMDR-TBpatientswere followed-upinMicronesia

Ofthe104whoinitiatedtreatment,93 (89%)completedtheregimen

Nonereceivingtreatmentdevelopedactive TB.3of15contactswhorefusedand15 unidentifiedcontactsdevelopedMDR-TB WhenM.tuberculosisstrainswereresistant toisoniazid,rifampicinandethambutolthe regimenswereasfollows:Adultsaged>12 yearsreceivedoralmoxifloxacin400mg dailyandethambutol15mg/KgBWdailyfor 12monthsChildrenaged12yearsreceived orallevofloxacin20mg/KgBWdailyand ethambutol15mg/KgBWdailyfor12 monthsWhenM.tuberculosisstrainswere resistanttoisoniazid,rifampicin, pyrazinamide,ethambutoland streptomycintheregimenincluded: Adultsaged>12years:oralmoxifloxacin 400mgdailyfor12months;

Childrenaged12years:orallevofloxacin 20mg/kgBWdailyandoralethambutol20 mg/kgBWdailyfor12months

4contactsdiscontinueddueto adverseevents

Bamrahet al.(2014)

Caseseries close MDR-TBcontacts

PreventdevelopmentofTBafterexposure toanMDR-TBindexpatient

31childrenwithLTBIafterexposure,26 treatedwithlevofloxacinandpyrazinamide

12childrenrequiredtreatment changesbecauseofadverseevents.

Adler-Shohetetal. (2014) Caseseries (retrospective auditof paediatric management)

Theauditidentifiedbetween2006and 201023childrenin6centresofEngland whowerecontactsofconfirmedMDR-TB indexcases

Of23children,8werenon-infectedand12 withconfirmedLTBI,8(66.7%)weretreated with2drugsforamedianof6months (range6-12months)basedofthe drug-susceptibilitypatternoftheindexcase.No detailsoftheregimesareprovided

All12children(includingthe10 whocompletedthe24month follow-up)werewellanddidnot reportadverseeventsorTB

Williamsetal.(2013)

Caseseries OccupationalexposuretoMDRTBresistant torifampicin,isoniazid,streptomycin,and ethambutolinNewYorkCity

Sixteenhealthcareworkersentereda six-monthinvestigationaltrialofofloxacin (800mgaday)andpyrazinamide (1500mgaday)

14casesdiscontinuedLTBI treatmentafterlessthan6months; 13reportedoneormoreadverse events,includingarthralgia(7), gastrointestinaldistress(6)and hepatitis

ContactinvestigationandtreatmentoflatentTBinfectionin MDR-TBcontacts

While rates of DR-TB are proportionately higher in persons previouslytreatedforTB,theburdenofMDR-TBislargerinpersons whohaveneverbeentreatedforTB,aconsequenceoftransmission ofDRbacilliinthecommunity.Thus,54%ofMDR-TBoccursamong patients who had never received TB treatment (Kendall et al., 2015).Inonestudy7.8%ofhouseholdcontactsofMDR-TBpatients developedTB, mostlyoccurringwithinoneyearof indexcase’s diagnosis(Shahetal.,2014).Untilrecently,therewasnoconsensus toprovidepreventivetreatmenttocontactsofinfectiousMDR-TB patients, but this has changed in the new ATS/CDC/ERS/IDSA ClinicalPracticeGuideline(Nahidetal.,2019).Asystematicreview on21relevantpapersfoundthattheestimatedMDR-TBincidence reductionwas90%withpreventivetreatment(Marksetal.,2017). Hence, preventive treatment of MDR-TB contacts with LTBI is currentlyrecommendedbasedontheaboveobservation.

Several randomised clinical trials are currently ongoing to determinea single-drugpreventivetreatmentregimenfor MDR-TB contacts; these are the PHOENIx trial (delamanid versus isoniazid) and theV-QUIN andTB- CHAMP clinical trials (levo-floxacinversusplaceboinadultsandchildren,respectively).While resultsofthesetrialsareawaited,preventivetreatmentshouldbe determinedonthebasisoftheDSTresultsofthesource-case’sM. tuberculosisisolate.

Ifpossible,alater-generationfluoroquinolonealoneorwitha second drugsuch as ethambutolshould be used (Nahid et al., 2019). Pyrazinamide should not be used as the second drug, because of higher adverse events and discontinuations. The evidence available is summarised in Table 2. (Adler-Shohet etal.,2014;Bamrahetal.,2014;Hornet al.,1994;Marksetal., 2017;Papastavrosetal., 2002;Seddon et al.,2013;Trieuetal., 2015;Williamsetal.,2013;Younossianetal.,2005).

Functionalevaluationandrehabilitationpost-TB

Recent evidence shows that about half of pulmonary TB patientscompletingtreatmentsufferfromtheconsequences of sequelae with obstructive, restrictive and mixed functional patterns(Muñoz-Torricoetal.,2016;Tiberietal.,2019).

Theextentofpulmonarysequelaeislikelytobeassociatedwith initialbacterialburden,extentofinflammationandthe accompa-nyingdurationoftreatment,beingmoreimportantamongMDR-/ XDR-TBpatients(especiallyiftheyhadpriorepisodesofTB)than amongdrug-susceptibleones(Muñoz-Torricoetal.,2016;Tiberi etal.,2019).

A complete post-TB treatment functional evaluation has beenrecommendedincludingradiology,spirometrywith bron-chodilatorresponse,assessmentof lungvolumes (plethysmog-raphy),carbonmonoxidediffusioncapacityofthelung(DLCO), arterialblood gases analysis; 6-min walking test(6MWt) and

qualityoflifeevaluation(Muñoz-Torricoetal.,2016;Tiberietal., 2019).

Pulmonaryrehabilitationprovedtobeeffectivein improving theabove-mentionedparameters(Spruitetal.,2013;Viscaetal., 2019).Further researchis necessary toidentifysetting-specific models and programmatic feasibility of these interventions (Muñoz-Torrico et al., 2016; Spruit et al., 2013; Tiberi et al., 2019;Viscaetal.,2019).

Publichealthmanagement

The principles of public health management are centered aroundachievinghighsuccessrateswhentreating drug-suscepti-ble cases and tryingtodiagnose and cure thehighest possible proportion of cases with MDR-TB while preventing further transmissionwithinthecommunity(Pontalietal.,2013).

Theimportanceof administrativeandenvironmental control measuresaswellasofpersonalprotection(masksforinfectious patientsandrespiratorstoprotecthealthcareworkersandvisitors frompotentialinfections)hasbeenrecentlyemphasised(Migliori etal.,2019;Migliorietal.,2018;WorldHealthOrganization,2019). WHOstronglyadvocatesforareductionofunnecessaryadmissions ofMDR-/XDR-TBcaseswhichneedtobelimitedtoseverecases withlife-threateningconditions,adverseeventsand co-morbid-ities, while reducing as much as possible admission for ‘social reasons’(Migliorietal.,2019;Migliorietal.,2018;WorldHealth Organization, 2019). Recent WHO European guidance provides criteria for units admitting infectious cases, including the availabilityandnecessarystandardsofinfectioncontrolmeasures, quality-controlledlaboratoryservices,adequatelytrainedstaffand palliativecareservice,amongothers(Migliorietal.,2019;Migliori etal.,2018;WorldHealthOrganization,2019).

Fromaprogrammaticperspectiveallthenecessarycomponents requiredtodiagnoseandtreatMDR-TBshouldworkadequately withinacoherentNationalStrategicPlan(WorldHealth Organi-zation, 2015b): quality-controlled laboratory network; drug procurement;clinicalservices;surveillance,andmonitoring and evaluation.

Conclusions

Althoughasignificantadvanceindiagnosisandtreatmenthas been achieved with the existing (and new) rapid molecular diagnostics,aswellaswiththeBPaLshortenedregimen,further researchinvestmentsarenecessaryonfastpatienttriageand all-oral shorter and better tolerated regimens. On top of further improvingtheexistingdiagnostic,treatmentandpreventiontools, universalaccessandcorrectprogrammaticuseareneededinall settings, inorder toimplement thethree pillarsof theEndTB strategy (1.Integrated, patient-centred care and prevention; 2. Bold policies and support systems; 3. Intensified research and innovation)andmeetitsgoalandtargets.

Table2(Continued)

Study/trial Studypopulation/Aim Design/treatment Adverseeventsandoutcome Reference

Caseseries Seventeenindividualswith presumedLTBIMDR-TBinfection

Treatedwithpyrazinamide andlevofloxacin

Fourteenindividualsdeveloped musculoskeletaladverseevents (11probablyrelatedtocombination therapy)and8centralnervousones Hyperuricemia,gastrointestinal anddermatologicaleffectswere alsocommon.Therapywas discontinuedinallofthem

Papastavrosetal. (2002)

MDR-TB:multidrug-resistanttuberculosis;LTBI:latenttuberculosisinfection;PICO:population,intervention,comparison,andoutcome;ALT-AST:alanineaminotransferase andaspartateaminotransferase;BW:bodyweight.

Conflictofintereststatement Nocompetinginterestdeclared. Fundingsources

Thisresearchdidnotreceiveanyspecificgrantfromfunding agenciesinthepublic,commercial,ornot-for-profitsectors. Ethicalapproval

Approvalwasnotrequired. Acknowledgements

This articleis partof a supplemententitled Commemorating WorldTuberculosisDayMarch24th,2020:“IT’STIMETOFIND,TREAT ALL and END TUBERCULOSIS!” published with support from an unrestrictededucationalgrantfromQIAGENSciencesInc. AppendixA.

The Global Tuberculosis Network (GTN) Collaborators who contributedtothisarticleare:

T. Abu Arkub (Russian Federation); O.W. Akkerman (Netherlands);A.Aleksa(Belarus);E.Belilovski(Russian Federa-tion); E. Bernal (Spain); F-X. Blanc (France); M. Boeree (Netherlands); S. Borisov (Russian Federation); J. Bruchfeld (Sweden);J.CadiñanosLoidi(Spain);J.A.Caminero(Spain);A.C. Carvalho(Brazil);J.J.CebrianGallardo(Spain);M.Charalampos (Greece); E.Danila (Lithuania); L.Davies Forsman (Sweden); J. Denholm (Australia); K. Dheda (S.Africa); R.Diel (Germany); S. Diktanas(Lithuania);C.Dobler(Australia);M.Enwerem(S.Africa); S.Esposito(Italy);N.EscobarSalinas(Chile);A.Filippov(Russian Federation); B. Formenti (Italy); J.M, García García (Spain); D. Goletti(Italy);R.GomezRosso(Paraguay);G.Gualano (Italy);P. Isaakidis(S.Africa);A.Kaluzhenina(RussianFederation);S.Koirala (Nepal);L.Kuksa(Latvia);H.Kunst(UK);Y.Li(China);C. Magis-Escurra (Netherlands); V. Manfrin (Italy); S. Manga (Peru); K. Manika(Greece);V.Marchese(Italy);E.MartínezRobles(Spain); A. Maryandyshev (Russian Federation); A. Matteelli (Italy); A. Mariani(Brazil);J.Mazza-Stalder(Switzerland);F.Mello(Brazil);L. Mendoza(Chile);A.Mesi(Albania);S.Miliauskas(Lithuania);H. MustafaHamdan(Sudan);N.Ndjeka (S.Africa);M.NietoMarcos (Spain);T.H.M.Ottenhoff(Netherlands);D.J.Palmero(Argentina);F. Palmieri(Italy);A.Papavasileiou(Greece);M.CPayen(Belgium);A. Pontarelli(Italy);M.PrettiDalcolmo(Brazil);S.QuirósFernandez (Spain);R.Romero(S.Africa);D.RossatoSilva(Brazil);A.P.Santos (Brazil);B.Seaworth(USA);M.Sinitsyn(RussianFederation);A. Skrahina(Belarus);I.Solovic(Slovakia);A.Spanevello(Italy);M. Tadolini(Italy);C.Torres(Colombia);Z.Udwadia(India);M.van denBoom(Denmark);G.V.Volchenkov(RussianFederation);A. Yedilbayev (Denmark); R. Zaleskis (Latvia); J.P. Zellweger (Switzerland).

This article belongs to the scientific activities of the WHO CollaboratingCentreforTuberculosisandLungDiseases,Tradate, ITA-80,2017-2020-GBM/RC/LDA.

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